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Renal Failure Dec 2024To explore the effect of lupus nephritis (LN) on graft survival in renal transplant patients. Literature search was conducted in PubMed, EMBASE and Scopus database for... (Meta-Analysis)
Meta-Analysis Review
To explore the effect of lupus nephritis (LN) on graft survival in renal transplant patients. Literature search was conducted in PubMed, EMBASE and Scopus database for randomized controlled trials (RCTs), cohort, and case-control studies. The target population of interest was adult patients (aged >18 years) with end-stage renal disease (ESRD) and no history of previous renal transplants. Primary outcomes of interest were graft survival and patient survival. Pooled effect estimates were calculated using random-effects models and reported as hazard ratio (HR) with 95% confidence intervals (CI). A total of 15 studies were included. Compared to patients with ESRD due to other causes, patients with LN undergoing kidney transplant had lower patient survival rate (HR 1.15, 95% CI: 1.01, 1.31; = 15, I=34.3%) and worse graft survival (HR 1.06, 95% CI: 1.01, 1.11; = 16, I=0.0%), especially when studies with deceased donor were pooled together. Studies with a larger sample size (>200) showed that LN was strongly associated with lower graft and patient survival rates. Elevated risk of mortality in LN patients was detected in case-control studies, but not RCTs. On the other hand, RCTs, but not case-control studies, showed an increased risk of poor graft survival in LN patients. The findings suggest that the presence of LN might have a negative impact on both the graft survival and the overall patient survival of post-transplant ESRD patients. Further studies that account for factors such as study methodology, donor characteristics, and sample size are needed to reach definitive conclusions. Renal transplant patients with LN should undergo regular follow-up examinations.
Topics: Adult; Humans; Case-Control Studies; Graft Survival; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Retrospective Studies
PubMed: 38178546
DOI: 10.1080/0886022X.2023.2296000 -
Reviews on Environmental Health Mar 2024One of the main factors that causes health effects in humans such as hospital admissions for cardiovascular disease (HACVD), respiratory disease (RD), lung function,... (Meta-Analysis)
Meta-Analysis Review
One of the main factors that causes health effects in humans such as hospital admissions for cardiovascular disease (HACVD), respiratory disease (RD), lung function, cardiovascular mortality (MCVD), lung cancer, and increased mortality is air pollution especially particulate matter (PM). This a systematic review and meta-analysis aims to investigate the effects of particulate matter on the occurrence of cardiovascular disease and mortality. A systematic review and meta-analysis of the literature was done from 2011 to 2021 based on various databases. Based on the result of this study, subgroup analysis based on temperature conditions showed a different estimation in cold cities (6.24, UR (4.36-8.12)), moderate cities (4.86, UR (3.57-6.15)) and warm cities (8.96, UR (7.06-10.86)). Test of group differences showed a significant difference (Q=12.22, p-value<0.001). There was publication bias among the studies (the Egger's test; (Z=14.18, p<0.001)). According result study pooled estimation of AP% for MCVD from the random-effect meta-analysis based on DerSimonian-Laird model, overall is 5.04, UR (3.65-6.43) (Figure 4). Subgroup analysis based on temperature conditions showed the estimation in cold cities (5.47, UR (3.97-6.97)) and moderate cities (4.65, UR (0.54-8.77)). Test of group differences showed a non-significant difference (Q=0.13, p-value=0.71). There was no publication bias among the studies (the Egger's test; (Z=0.82, p=0.376)). Exposed to air pollutants and particulate matter can be increase the risk of cardiovascular disease, respiratory disease, and cardiovascular mortality.
Topics: Humans; Air Pollutants; Air Pollution; Cardiovascular Diseases; Cities; Particulate Matter; Environmental Exposure
PubMed: 36302126
DOI: 10.1515/reveh-2022-0090 -
BMC Medicine Mar 2024The impact of sodium intake on cardiovascular disease (CVD) health and mortality has been studied for decades, including the well-established association with blood... (Meta-Analysis)
Meta-Analysis
Sex-specific associations between sodium and potassium intake and overall and cause-specific mortality: a large prospective U.S. cohort study, systematic review, and updated meta-analysis of cohort studies.
BACKGROUND
The impact of sodium intake on cardiovascular disease (CVD) health and mortality has been studied for decades, including the well-established association with blood pressure. However, non-linear patterns, dose-response associations, and sex differences in the relationship between sodium and potassium intakes and overall and cause-specific mortality remain to be elucidated and a comprehensive examination is lacking. Our study objective was to determine whether intake of sodium and potassium and the sodium-potassium ratio are associated with overall and cause-specific mortality in men and women.
METHODS
We conducted a prospective analysis of 237,036 men and 179,068 women in the National Institutes of Health-AARP Diet and Health Study. Multivariable-adjusted Cox proportional hazard regression models were utilized to calculate hazard ratios. A systematic review and meta-analysis of cohort studies was also conducted.
RESULTS
During 6,009,748 person-years of follow-up, there were 77,614 deaths, 49,297 among men and 28,317 among women. Adjusting for other risk factors, we found a significant positive association between higher sodium intake (≥ 2,000 mg/d) and increased overall and CVD mortality (overall mortality, fifth versus lowest quintile, men and women HRs = 1.06 and 1.10, P < 0.0001; CVD mortality, fifth versus lowest quintile, HRs = 1.07 and 1.21, P = 0.0002 and 0.01). Higher potassium intake and a lower sodium-potassium ratio were associated with a reduced mortality, with women showing stronger associations (overall mortality, fifth versus lowest quintile, HRs for potassium = 0.96 and 0.82, and HRs for the sodium-potassium ratio = 1.09 and 1.23, for men and women, respectively; P < 0.05 and both P for interaction ≤ 0.0006). The overall mortality associations with intake of sodium, potassium and the sodium-potassium ratio were generally similar across population risk factor subgroups with the exception that the inverse potassium-mortality association was stronger in men with lower body mass index or fruit consumption (P < 0.0004). The updated meta-analysis of cohort studies based on 42 risk estimates, 2,085,904 participants, and 80,085 CVD events yielded very similar results (highest versus lowest sodium categories, pooled relative risk for CVD events = 1.13, 95% CI: 1.06-1.20; P < 0.001).
CONCLUSIONS
Our study demonstrates significant positive associations between daily sodium intake (within the range of sodium intake between 2,000 and 7,500 mg/d), the sodium-potassium ratio, and risk of CVD and overall mortality, with women having stronger sodium-potassium ratio-mortality associations than men, and with the meta-analysis providing compelling support for the CVD associations. These data may suggest decreasing sodium intake and increasing potassium intake as means to improve health and longevity, and our data pointing to a sex difference in the potassium-mortality and sodium-potassium ratio-mortality relationships provide additional evidence relevant to current dietary guidelines for the general adult population.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO Identifier: CRD42022331618.
Topics: Adult; Female; Humans; Male; Cohort Studies; Sodium; Cause of Death; Prospective Studies; Diet; Cardiovascular Diseases; Risk Factors; Sodium, Dietary; Potassium
PubMed: 38519925
DOI: 10.1186/s12916-024-03350-x -
BJOG : An International Journal of... Feb 2024A systematic review with met-analysis was performed to summarise the evidence on the effect of intrapartum azithromycin on maternal and neonatal infections and deaths. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
A systematic review with met-analysis was performed to summarise the evidence on the effect of intrapartum azithromycin on maternal and neonatal infections and deaths.
SEARCH STRATEGY
PubMed, Scopus and Web of Science databases were searched in March 2023.
SELECTION CRITERIA
Randomised controlled trials comparing intrapartum single-dose of azithromycin with placebo.
DATA COLLECTION AND ANALYSIS
Maternal infections, maternal mortality, neonatal sepsis, neonatal mortality. We used the random-effects Mantel-Haenszel method to calculate risk ratios (RR) with 95% confidence intervals (95% CI). We assessed risk of bias of the included studies and estimated the evidence certainty using the GRADE approach.
MAIN RESULTS
After screening 410 abstracts, five studies with 44 190 women and 44 565 neonates were included. The risk of bias was low in four and had some concerns in one of the studies. The risk of endometritis was 1.5% in the azithromycin group and 2.3% in the placebo group (RR 0.64, 95% CI 0.55-0.75), and the evidence certainty was high. The respective risk for chorioamnionitis was 0.05% and 0.1% (RR 0.50, 95% CI 0.22-1.18; evidence certainty moderate). The wound infection rate was lower in the azithromycin group (1.6%) than in the placebo group (2.5%), RR 0.52 (95% CI 0.30-0.89; moderate certainty evidence). The maternal sepsis rate was 1.1% in the azithromycin group and 1.7% in the placebo group (RR 0.66, 95% CI 0.56-0.77; evidence certainty high). Mortality rates did not show evidence of a difference (0.09% versus 0.08%; RR 1.26, 95% CI 0.65-2.42; moderate certainty evidence). The neonatal mortality rate was 0.7% in the azithromycin group and 0.8% in the placebo group (RR 0.94, 95% CI 0.76-1.16; moderate certainty evidence). The neonatal sepsis rate was 7.6% in the azithromycin group and 7.4% in the placebo group (RR 1.02, 95% CI 0.96-1.09; moderate certainty evidence).
CONCLUSIONS
Intrapartum administration of azithromycin to the mother reduces maternal postpartum infections, including sepsis. Impact on maternal mortality remains undecided. Azithromycin does not reduce neonatal sepsis or mortality rates.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Azithromycin; Chorioamnionitis; Neonatal Sepsis; Pregnancy Complications, Infectious; Sepsis; Randomized Controlled Trials as Topic; Peripartum Period
PubMed: 37691261
DOI: 10.1111/1471-0528.17655 -
Bulletin of the World Health... Sep 2023To conduct a systematic review of verbal autopsy studies in low- and middle-income countries to estimate the fraction of deaths due to cardiovascular disease. (Review)
Review
OBJECTIVE
To conduct a systematic review of verbal autopsy studies in low- and middle-income countries to estimate the fraction of deaths due to cardiovascular disease.
METHOD
We searched MEDLINE®, Embase® and Scopus databases for verbal autopsy studies in low- and middle-income countries that reported deaths from cardiovascular disease. Two reviewers screened the studies, extracted data and assessed study quality. We calculated cause-specific mortality fractions for cardiovascular disease for each study, both overall and according to age, sex, geographical location and type of cardiovascular disease.
FINDINGS
We identified 42 studies for inclusion in the review. Overall, the cardiovascular disease cause-specific mortality fractions for people aged 15 years and above was 22.9%. This fraction was generally higher for males (24.7%) than females (20.9%), but the pattern varied across World Health Organization regions. The highest cardiovascular disease mortality fraction was reported in the Western Pacific Region (26.3%), followed by the South-East Asia Region (24.1%) and the African Region (12.7%). The cardiovascular disease mortality fraction was higher in urban than rural populations in all regions, except the South-East Asia Region. The mortality fraction for ischaemic heart disease (12.3%) was higher than that for stroke (8.7%). Overall, 69.4% of cardiovascular disease deaths were reported in people aged 65 years and above.
CONCLUSION
The burden of cardiovascular disease deaths outside health-care settings in low- and middle-income countries is substantial. Increasing coverage of verbal autopsies in these countries could help fill gaps in cardiovascular disease mortality data and improve monitoring of national, regional and global health goals.
Topics: Female; Humans; Male; Autopsy; Cardiovascular Diseases; Developing Countries; Myocardial Ischemia; Stroke
PubMed: 37638359
DOI: 10.2471/BLT.23.289802 -
JAMA Jun 2024Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential... (Comparative Study)
Comparative Study Meta-Analysis
IMPORTANCE
Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening.
OBJECTIVE
To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening.
DESIGN, SETTING, AND PARTICIPANTS
This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer.
EXPOSURES
Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening.
MAIN OUTCOMES AND MEASURES
End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis.
RESULTS
The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P = .02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson ρ = -0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity = .004).
CONCLUSIONS AND RELEVANCE
In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.
Topics: Female; Humans; Male; Early Detection of Cancer; Endpoint Determination; Incidence; Neoplasm Staging; Neoplasms; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 38583868
DOI: 10.1001/jama.2024.5814 -
Journal of the American Heart... Dec 2023Veno-arterial extracorporeal membrane oxygenation serves as a crucial mechanical circulatory support for pediatric patients with severe heart diseases, but the mortality... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Veno-arterial extracorporeal membrane oxygenation serves as a crucial mechanical circulatory support for pediatric patients with severe heart diseases, but the mortality rate remains high. The objective of this study was to assess the short-term mortality in these patients.
METHODS AND RESULTS
We systematically searched PubMed, Embase, and Cochrane Library for observational studies that evaluated the short-term mortality of pediatric patients undergoing veno-arterial extracorporeal membrane oxygenation. To estimate short-term mortality, we used random-effects meta-analysis. Furthermore, we conducted meta-regression and binomial regression analyses to investigate the risk factors associated with the outcome of interest. We systematically reviewed 28 eligible references encompassing a total of 1736 patients. The pooled analysis demonstrated a short-term mortality (defined as in-hospital or 30-day mortality) of 45.6% (95% CI, 38.7%-52.4%). We found a significant difference (<0.001) in mortality rates between acute fulminant myocarditis and congenital heart disease, with acute fulminant myocarditis exhibiting a lower mortality rate. Our findings revealed a negative correlation between older age and weight and short-term mortality in patients undergoing veno-arterial extracorporeal membrane oxygenation. Male sex, bleeding, renal damage, and central cannulation were associated with an increased risk of short-term mortality.
CONCLUSIONS
The short-term mortality among pediatric patients undergoing veno-arterial extracorporeal membrane oxygenation for severe heart diseases was 45.6%. Patients with acute fulminant myocarditis exhibited more favorable survival rates compared with those with congenital heart disease. Several risk factors, including male sex, bleeding, renal damage, and central cannulation contributed to an increased risk of short-term mortality. Conversely, older age and greater weight appeared to be protective factors.
Topics: Humans; Male; Child; Extracorporeal Membrane Oxygenation; Myocarditis; Heart Defects, Congenital; Hemorrhage; Survival Rate; Retrospective Studies
PubMed: 38063152
DOI: 10.1161/JAHA.123.029571 -
BMJ Supportive & Palliative Care May 2024Lung cancer is one of the most common malignant tumours. Patients are frequently at risk of frailty as lung cancer progresses. The meta-analysis aims to explore the... (Meta-Analysis)
Meta-Analysis
Lung cancer is one of the most common malignant tumours. Patients are frequently at risk of frailty as lung cancer progresses. The meta-analysis aims to explore the impact of frailty on the long-term prognosis and the incidence of short-term chemotherapy toxicity in patients with lung cancer. This study was designed adhered to the criteria of Cochrane Handbook for Systematic Reviews. Systematic searches were performed on PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies until December 2022. The outcome measures were overall survival, progression-free survival, chemotherapy toxicity and all-cause mortality. We then performed sensitivity analyses, subgroup analyses and evidence quality. This meta-analysis was performed using Review Manager V.5.4 software. Of the included studies, six were retrospective and five were prospective. There was a statistically significant difference between the frail and non-frail groups in overall survival (HR 2.27, 95% CI 1.24 to 4.15, p=0.008), all-cause mortality (HR 1.63, 95% CI 1.00 to 2.65, p=0.05) and chemotherapy toxicity (OR 3.73, 95% CI 1.99 to 7.00, p<0.0001). We conducted a sensitivity analysis, and the result was stable. The study revealed frail group had shorter survival and experienced more severe adverse effects than the non-frail group. Frailty affects the long-term prognosis and the incidence of short-term chemotherapy toxicity of patients with lung cancer. Consequently, medical professionals should focus on frailty screening in patients with lung cancer and implement active intervention measures. PROSPERO registration number is CRD42023398606.
Topics: Humans; Lung Neoplasms; Prognosis; Frailty
PubMed: 38050057
DOI: 10.1136/spcare-2023-004577 -
American Journal of Obstetrics &... Dec 2023This study aimed to compare maternal outcomes of prenatally and nonprenatally diagnosed placenta accreta spectrum. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to compare maternal outcomes of prenatally and nonprenatally diagnosed placenta accreta spectrum.
DATA SOURCES
A systematic literature search was performed in PubMed, the Cochrane database, and Web of Science until November 28, 2022.
STUDY ELIGIBILITY CRITERIA
Studies comparing the clinical presentation of prenatally and nonprenatally diagnosed placenta accreta spectrum were included. The primary outcomes were emergent cesarean delivery, hysterectomy, blood loss volume, number of transfused blood product units, urological injury, coagulopathy, reoperation, intensive care unit admission, and maternal death. In addition, the pooled mean values for blood loss volume and the number of transfused blood product units were calculated. The secondary outcomes included maternal age, gestational age at birth, nulliparity, previous cesarean delivery, previous uterine procedure, assisted reproductive technology, placenta increta and percreta, and placenta previa.
METHODS
Study screening was performed after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis.
RESULTS
Overall, 415 abstracts and 157 full-text studies were evaluated. Moreover, 31 studies were analyzed. Prenatally diagnosed placenta accreta spectrum was associated with a significantly lower rate of emergency cesarean delivery (odds ratio, 0.37; 95% confidence interval, 0.21-0.67), higher hysterectomy rate (odds ratio, 1.98; 95% confidence interval, 1.02-3.83), lower blood loss volume (mean difference, -0.65; 95% confidence interval, -1.17 to -0.13), and lower number of transfused red blood cell units (mean difference, -1.96; 95% confidence interval, -3.25 to -0.68) compared with nonprenatally diagnosed placenta accreta spectrum. The pooled mean values for blood loss volume and the number of transfused blood product units tended to be lower in the prenatally diagnosed placenta accreta spectrum groups than in the nonprenatally diagnosed placenta accreta spectrum groups. Nulliparity (odds ratio, 0.14; 95% confidence interval, 0.10-0.20), previous cesarean delivery (odds ratio, 6.81; 95% confidence interval, 4.12-11.25), assisted reproductive technology (odds ratio, 0.19; 95% confidence interval, 0.06-0.61), placenta increta and percreta (odds ratio, 3.97; 95% confidence interval, 2.24-7.03), and placenta previa (odds ratio, 6.81; 95% confidence interval, 4.12-11.25) showed statistical significance. No significant difference was found for the other outcomes.
CONCLUSION
Despite its severity, the positive effect of prenatally diagnosed placenta accreta spectrum on outcomes underscores the necessity of a prenatal diagnosis. In addition, the pooled mean values provide a preoperative preparation guideline.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Placenta Accreta; Placenta Previa; Cesarean Section; Intensive Care Units; Maternal Mortality
PubMed: 37865220
DOI: 10.1016/j.ajogmf.2023.101197 -
The Lancet. Diabetes & Endocrinology Jul 2024Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups.
METHODS
In this systematic review and meta-analysis, we queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. This study is registered with PROSPERO, CRD42024513836.
FINDINGS
We included 15 trials (N=100 952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0·71 [95% CI 0·67-0·77]), 28% in patients with type 2 diabetes (0·72 [0·67-0·77]), 32% in patients with chronic kidney disease (0·68 [0·61-0·77]), and 28% in patients with atherosclerotic cardiovascular disease (0·72 [0·66-0·79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79-0·93]), 15% in patients with type 2 diabetes (0·85 [0·79-0·91]), 11% in patients with chronic kidney disease (0·89 [0·82-0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78-0·97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death).
INTERPRETATION
SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors.
FUNDING
None.
Topics: Sodium-Glucose Transporter 2 Inhibitors; Humans; Heart Failure; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Renal Insufficiency, Chronic; Hospitalization
PubMed: 38768620
DOI: 10.1016/S2213-8587(24)00102-5